Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/20—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/08—Mydriatics or cycloplegics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/20—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/16—Peri-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/10—Spiro-condensed systems

Definitions

• AD Alzheimer's disease
• ⁇ -Amyloid deposits are predominantly an aggregate of A ⁇ peptide, which in turn is a product of the proteolysis of amyloid precursor protein (APP). More specifically, A ⁇ peptide results from the cleavage of APP at the C-terminals by one or more ⁇ -secretases, and at the N-terminus by ⁇ -secretase enzyme (BACE), also known as aspartyl protease, as part of the ⁇ -amyloidogenic pathway.
• BACE ⁇ -secretase enzyme
• BACE activity is correlated directly to the generation of A ⁇ peptide from APP, and studies increasingly indicate that the inhibition of BACE inhibits the production of A ⁇ peptide.
• Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders including dementia-inducing disorders.
• Amyloid- ⁇ (A ⁇ ) has been reported to be implicated in the development of RGC apotosis in glaucoma, with evidence of caspase-3-mediated abnormal amyloid precursor protein processing, increased expression of A ⁇ in RGCs in experimental glaucoma and decreased vitreous A ⁇ levels (consistent with retinal A ⁇ deposition) in patients with glaucoma.
• the present invention provides compounds that are BACE inhibitors and are useful as therapeutic agents in the treatment, prevention and amelioration of a disease or disorder characterized by elevated ⁇ -amyloid deposits or ⁇ -amyloid levels in a patient.
• WO 2008/030412 discloses different beta-secretase inhibitors for use in treating glaucoma and/or Alzheimer's disease, but the central structures of the compounds disclosed therein are not fused to a phenyl ring compared to the compounds of the invention.
• the present invention relates to compounds represented by the following Structural Formula: or a pharmaceutically acceptable salt thereof, wherein:
• compounds of the invention is represented by Structural Formula (I'): or a pharmaceutically acceptable salt thereof, wherein:
• One embodiment of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof).
• a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof).
• Another embodiment is a compound of the invention for use in a method of inhibiting BACE activity in a subject in need of such treatment.
• the method comprises administering to the subject an effective amount of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof).
• a BACE inhibitor disclosed herein e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof.
• Another embodiment is a compound of the invention for use in a method of treating a BACE mediated disorder in a subject.
• the method comprises administering to the subject an effective amount of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof).
• a BACE inhibitor disclosed herein e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof.
• Another embodiment is a compound of the invention for use in a method of of treating a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject in need of such treatment comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound represented by Structural Formula (I) or (I') or a pharmaceutically acceptable salt thereof).
• a compound disclosed herein e.g., a compound represented by Structural Formula (I) or (I') or a pharmaceutically acceptable salt thereof.
• Another embodiment of the invention is the use of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for inhibiting BACE activity in a subject.
• a BACE inhibitor disclosed herein e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof
• Another embodiment of the invention is the use of a BACE inhibitor disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for treating a BACE mediated disorder in a subject.
• a BACE inhibitor disclosed herein e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof
• Another embodiment of the invention is the use of a compound disclosed herein (e.g., a compound represented by Structural Formula (I) or (I'), or a pharmaceutically acceptable salt thereof) for the manufacture of a medicament for treating a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject.
• a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject.
• the present invention is directed to compounds represented by the Structural Formula (I) or a phamaceutically acceptable salt thereof.
• Values and particular values for the variables in Structural Formula I or an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof are provided in the following paragraphs. It is understood that the invention encompasses all combinations of the substituent variables (i.e., R 1 , R 2 , R 3 , etc.) defined herein.
• R 2 is -H, -Cl, -Br or -F.
• R 2 is (C 1 -C 6 )alkyl. More particularly, R 2 is (C 1 -C 3 )alkyl.
• the substituents are independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl,, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl.
• the substituents are independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 3 )alkyl, a 5-6 membered aryl or heteroaryl. Even more specifically, the substituents are independently selected from the group -F, -Cl, -Br, -CN, (C 1 -C 3 )alkyl, pyrrolyl and imidazolyl.
• R 3 and R 4 are each idependently -H, -F, -Br, -Cl or (C 1 -C 6 )alkyl optionally substituted with an aryl group or a heteraryl group.
• R 3 and R 4 are both -H.
• R 3 and R 4 are independently -H, -F or methyl.
• one of R 3 and R 4 are -H, the other is a (C 1 -C 6 )alkyl optionally susbstituted with a phenyl group, where the phenyl group is optionally substituted with 1-3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl.
• R 5 is -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloheteroalkyl, aryl, heteroaryl, or benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1
• R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloheteroalkyl or benzyl.
• R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, pyrrolidinyl or benzyl. More particlular, R 5 is methyl, ethyl, propyl, butyl, methoxypropyl, methoxyethyl, benzyl or pyrrolidinyl.
• each R 6 and R 7 are independently -H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl.
• R 6 and R 7 are each independently -H or (C 1 -C 6 )alkyl.
• R 6 and R 7 are both -H.
• R 8 and R 9 are both -H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. More particluarly, R 8 and R 9 are both -H, methyl or hydroxymethyl.
• R 8 is a (C 1 -C 6 )alkyl optionally substituted with1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )cycloheteroalkyl.
• substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl.
• one of R 8 and R 9 is -H, the other one is a (C 1 -C 3 )alkyl optionally substituted(C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran or tetrahydropyran).
• R 8 is a (C 2 -C 6 )alkenyl optionally substituted with1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )cycloheteroalkyl. More particularly, substituents are selected from the group consisting of (C 1 -C 3 )alkyl and hydroxy(C 1 -C 3 )alkyl.
• R 9 when R 9 is -H, R 8 unsubstituted phenyl.
• R 9 when R 9 is -H, R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl. More particularly, the substituents independently selected from -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy.
• R 8 is (C 3 -C 14 )cyloalkyl (preferrably monocyclic (C 3 -C 8 )cycloalkyl such as cyclopentyl and cyclohexyl, or bicyclic fused (C 9 -C 14 )cycloalkyl, such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), (C 3 -C 13 )cycloheteroalkyl (preferrably monocyclic (C 3 -C 7 )cycloheteroalkyl such as tetrahydrofuran, tetrahydropyran and piperidine, or bicyclic fused or bridged (C 8 -C 13 )cycloheteroalkyl such as 5,6,7,8-te
• R 8 is unsubstituted (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl).
• R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each of which is optionally substituted with (C 1 -C 6 )alkyl, preferably methyl.
• ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo
• ring A is a 5-7 membered monocyclic ring optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl. (C 1 -C 6 )alkoxy and (C 1 -C 3 )alkylcarbonyl.
• ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring optionally subsituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxN, and (C 1 -C 3 )alkylcarbonyl.
• ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7.8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy and (C 1 -C 3 )alkylcarbony
• R 11 is -H, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl. In a particular embodiment, R 11 is -H.
• Each R 12 and R 13 are independently -H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl.
• R 12 and R 13 are independently -H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, cyano(C 1 -C 3 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl. More particularly, R 12 and R 13 are independently -H, methyl, ethyl, propyl, butyl, methoxyethyl, cyanoethyl, or dimethylaminoethyl.
• R 14 is -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, cycloheteroalkyl(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl.
• R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl.
• R 14 is methyl.
• R 15 is -H or (C 1 -C 6 )alkyl. In a particular embodiment, R 15 is -H.
• R 16 and R 17 are each independently -H or (C 1 -C 3 )alkyl. In a particular embodiment, R 16 and R 17 are both -H.
• R 18 is -H or (C 1 -C 3 )alkyl. In a particular embodiment, R 18 is -H.
• X is -O-, -S-, -SO-, -SO 2 -, -CH 2 O-, or -OCH 2 -.
• X is -O-.
• X is -S-.
• X is -SO-.
• X is -SO 2 -.
• Y is -C(R 8 R 9 )-.
• W is -N(R 14 )-, -S-, or -O-. In a particular embodiment, W is -N(R 14 )-.
• Z is -O-.
• i 0, 1 or 2;
• p is 1 or 2. In a particular embodiment, p is 1.
• n 1 or 2.
• n 1 or 2. In a particular embodiment, n is 1.
• One embodiment of the present invention is directed to compounds represented by the Structural Formula (I') or a phamaceutically acceptable salt thereof.
• Values and particular values for the variables in Structural Formula (I') or an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof are provided in the following paragraphs. It is understood that the invention encompasses all combinations of the substituent variables (i.e., R 1 , R 2 , R 3 , etc.) defined herein.
• R 1 is -H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or heteroaryl(C 1 -C 6 )alkyl. In one embodiment R 1 is -H, (C 1 -C 6 )alkyl or benzyl. In another embodiment, R 1 is -H.
• R 2 is -H, -Cl, -Br or -F.
• R 2 is (C 1 -C 6 )alkyl. More particularly, R 2 is (C 1 -C 3 )alkyl.
• R 3 and R 4 are each idependently -H, -F, -Br, -Cl or (C 1 -C 6 )alkyl. In a particular embodiment, R 3 and R 4 are both -H. In another particular embodiment, R 3 and R 4 are independently -H, -F or methyl.
• R 5 is -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloallcyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 7 ) cycloheteroalkyl, aryl, heteroaryl, or benzyl, each of which is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C6)alkyl, (C 1 -C 3 )alkoxy, halo(C 1
• R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, (C 3 -C 7 )cycloheteroalkyl or benzyl.
• R 5 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, pyrrolidinyl or benzyl. More particlular, R 5 is methyl, ethyl, propyl, butyl, methoxypropyl, methoxyethyl, benzyl or pyrrolidinyl.
• R 6 and R 7 are each independently -H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl.
• R 6 and R 7 are each independently -H or (C 1 -C 6 )alkyl. In another particular embodiment, and R 7 are both -H.
• R 9 is -H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. More particluarly, R 9 is -H, methyl or hydroxymethyl. In another particular embodiment, when R 9 is -H, R 8 is unsubstituted phenyl.
• R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy. More particularly, the substituents independently selected from -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy.
• R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.
• R 8 is unsubstituted (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl).
• R 8 is (C 3 -C 8 )cyloalkyl(preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and
• R 8 is independently selected from hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy and R 9 is independently selected from -H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )
• R 8 is selected from hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, phenyl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy and R 9 is independently selected from -H, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, phenyl or
• ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.
• ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, or piperidine, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkylcarbonyl.
• R 11 is -H, (C 1 -C 6 )alkyl or halo(C 1 -C 6 )alkyl. In a particular embodiment, R 11 is -H.
• R 12 and R 13 are each independently -H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl.
• R 12 and R 13 are independently -H, (C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, cyano(C 1 -C 3 )alkyl, or di(C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl. More particularly, R 12 and R 13 are independently -H, methyl, ethyl, propyl, butyl, methoxyethyl, cyanoethyl, or dimethylaminoethyl.
• R 14 is -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, cycloheteroalkyl(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl, aryl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl and (C 1 -C 3 )alkoxy.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl.
• R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl.
• R 14 is methyl.
• R 15 is -H or (C 1 -C 6 )alkyl. In a particular embodiment, R 15 is -H.
• R 16 and R 17 are each independently -H or (C 1 -C 3 )alkyl. In a particular embodiment, R 16 and R 17 are both -H.
• R 18 is -H or (C 1 -C 3 )alkyl. In a particular embodiment, R 18 is -H.
• X is -0-, -S-, -SO-, -SO 2 -, -CH 2 O-, or -OCH 2 -. In a particular embodiment, X is -O-. Iri another particular embodiment, X is -S-. In another particular embodiment, X is -SO-. In another particular embodiment, X is -SO 2 -.
• Y is -C(R 8 R 9 )-.
• W is -N(R 14 )-, -S-, or -O-. In a particular embodiment, W is -N(R 14 )-.
• Z is -O-.
• i 0, 1 or 2;
• p is 1 or 2. In a particular embodiment, p is 1.
• n 1 or 2.
• n 1 or 2. In a particular embodiment, n is 1.
• the compound of the present invention is represented by Structural Formula (II):
• Ring A is an optionally subsituted 3-14 membered monocyclic ring, 9-14 membered bicyclic ring or 9-14 membered polycyclic ring. Values and particular values for the remainder of the variables in Structural Formula (II) are as described above for Structural Formula (I).
• Ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy or halo(C 1 -C
• Ring A is an optionally subsituted 3-8 membered ring containing 0 to 3 heteroatoms, which are independently selected from O, N and S; wherein when the heteroatom is nitrogen, the nitrogen is substituted with -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl, and when the heteroatom is sulfur, the sulfur is optionally mono-or di-oxygenated.
• Values and particular values for the remainder of the variables in Structural Formula (II) are as described above for Structural Formula (I').
• Ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.
• the compound of the present invention is represented by the following Structural Formulas: Values and particular values for Structural Formulas (III), (IV), (V), (VI), (VII) and (XIV) are as described above for Structural Formula (II) in the 1 st specific embodiment. More specifically, R 2 is independently -H, -F, -Cl or -Br and p is 2.
• the compound of the present invention is represented by the following Structural Formulas: Values and particular values for Structural Formulas (IIIa), (IVa), (Va), (VIa), (VIIa) and (XIVa) are as described above for Structural Formula (II).
• X is -O-, and the values and specific values of the remainder of the variable are as described in the 3 rd specific embodiment.
• X is -S-, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.
• X is -SO-, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.
• X is -SO 2 -, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.
• R 2 is -H, -Cl, -Br, -F or (C 1 -C 6 )alkyl, and the values and specific values of the remainder of the variable are as described above in the 3 rd specific embodiment.
• R 2 is -H, -Cl, -Br, -F or (C 1 -C 6 )alkyl and X is -O-. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.
• R 2 is -H, -Cl, -Br, -F or (C 1 -C 6 )alkyl and X is -S-. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.
• R 2 is -H, -Cl, -Br, -F or (C 1 -C 6 )alkyl and X is -SO-. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.
• R 2 is -H, -Cl, -Br, -F or (C 1 -C 6 )alkyl and X is -SO 2 -. Values and specific values of the remainder of the variable are as described above in the 4 th specific embodiment.
• ring A a 5-7 membered monocyclic ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy
• ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally subsituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -
• ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl.
• Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa), and (XIVa), are as described above in the 4 th specific embodiment.
• X is -O-.
• X is -O-; and R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl. In another even more specific embodiment, X is -O-; and R 14 is methyl.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline
• X is -O-.
• X is -O-;
• R 14 is ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl;
• ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, or piperidine.
• R 2 is cyclohexyl, pyrrolidinyl, pyridinyl, pyrimidinyl, thiophenyl or thiazolyl.
• the substituents are independently selected from -F, -Cl, -Br, -CN, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy ,(C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, phenyl and 5-6 membered heteroaryl (preferrably pyridine or pyrimidine).
• X is -O-, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.
• X is -S-, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.
• X is -SO-, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.
• X is -SO 2 -, and the values and specific values of the remainder of the variable are as described in the 5 th specific embodiment.
• ring A a 5-7 membered monocyclic ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy
• ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally subsituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -CI, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -
• ring A is selected from tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, and 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 subsituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alky
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl.
• Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa) and (VIa) are as described above in the 5 th specific embodiment.
• X is -O-.
• X is -O-; and R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; R 3 and R 4 are -H; and R 1 is -H.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or
• X is -O-.
• X is -O-;
• R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl;
• ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydrona
• R 2 is aryl and values and specific values for the remainder of the variables are as described above in the 3 rd specific embodiment. More specifically, R 2 is phenyl.
• X is -O-, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.
• X is -S-, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.
• X is -SO-, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.
• X is -SO 2 -, and values and specific values for the remainder of the variables are as described above in the 6 th specific embodiment.
• ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2.3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 subsituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl,
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl.
• Values and specific values for the remainder of the variables in Structural Formulas (IIIa), (IVa), (VIa) and (XIVa), are as described above in the 6 th specific embodiment.
• X is -O-.
• X is -O-; and R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl; R 3 and R 4 are -H; and R 1 is -H.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-
• X is -O-.
• X is -O-;
• R 14 is methyl, ethyl, propyl, cyclohexylmethyl, cyclopropylethyl, trifluoroethyl, or benzyl;
• ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydrona
• ring A a 5-7 membered monocyclic ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally substituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl,
• ring A is a 9-14 membered bicyclic fused or bicyclic bridged ring containing 0 to 2 heteratoms independently selected from O, S and N, wherein ring A is optionally subsituted with 1 to 3 substituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 3 )alkylcarbonyl, 5-6 membered heteroaryl (preferrably pyridine or pyrimidine), phenyl, phenoxy and benzoxy, wherein the phenyl, phenoxy and benzoxy are each optionally substituted with -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C
• ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 subsituents independently selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl,
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl. Values and specific values for the remainder of the variables in Structural Formulas (IIIb), (IVb), (VIb) and (XIVb), are as described above in the 7 th specific embodiment. Even more specifically, R 14 is methyl.
• R 14 is (C 1 -C 6 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 3 )alkyl or benzyl; and ring A is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-
• R 14 is methyl
• R 1 is -H
• ring A is unsubstituted tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane.
• R 10 is -F, -Cl, -Br, -CN, -CF 3 , or -OR 5 ; and R 14 is methyl. Values and specific values for the remainder of the variables are as described above in the 8 th specific embodiment.
• the compounds of the present invention are represented by the following Structural Formulas: wherein R 8 is independently hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 14 )cycloalkyl, C 3 -C 13 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with one to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )
• R is independently hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, C 3 -C 7 )cycloheteroalkyl, aryl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F,-Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxyl(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, and R 9 is independently selected from the group consisting
• the compounds of the present invention are represented by the following Structural Formulas: Values and specific values for varibles for Strucutral Formulas (IX)-(XIII) and (XV) are as described above for Structural Formula (VIII) in the 9 th specific embodiment.
• X is -O-.
• R 2 is independently -H, -F, -Cl or -Br and p is 2.
• X is -O- and the values and specific values of the remainder of the variables are as described above in the 11 th specific embodiment.
• X is -S-, and the values and specific values of the remainder of the variables are as described above in the 11 th specific embodiment.
• X is -SO-, and the values and specific values of the remainder of the variables are as described in the 11 th specific embodiment.
• X is -SO 2 -, and the values and specific values of the remainder of the variables are as described in the 11 th specific embodiment.
• R 2 is -H, -Cl, -Br, -F or (C 1 -C 6 )alkyl, and the values and specific values of the remainder of the variable are as described above in the 11 th specific embodiment.
• X is -O-, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.
• X is -S-, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.
• X is -SO-, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.
• X is -SO 2 -, and the values and specific values of the remainder of the variable are as described above in the 12 th specific embodiment.
• R 8 is independently (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, phenyl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of-F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 )cycloalkyl and (C 3 -C 7 )cycloheteroalky
• R 8 is hydroxy(C 1 -C 3 )alkyl is -H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment.
• X is -O-.
• X is -O-, and R 9 is H, methyl or hydroxymethyl.
• R 8 is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.
• substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 12 th specific embodiment. More particularly, X is -O-. Even more particularly, when R 9 is -H, R 8 is a (C 1 -C 3 )alkyl optionally substituted(C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is -O-.
• R 8 is a (C 2 -C 6 )alkenyl optionally substituted with1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 - 8 )cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.
• R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl.
• X is -O-. In another even more specific embodiment, X is -O-; and when R 9 is -H, R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting independently selected from -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl.
• R 9 is -H
• R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicycic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7
• X is -O-.
• X is -O-; and R 9 is -H, R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroal
• X is -O-; when R 9 is -H, R 8 is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C
• R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.
• X is -O-. In another even more specific embodiment, X is -O-; and when R 9 is -H, R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 (C 1 -C 6 )alkyl.
• R 9 is -H
• R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl
• R 2 is cyclohexyl, pyrrolidinyl, pyridinyl, pyrimidinyl, thiophenyl or thiazolyl.
• the substituents are independently selected from -F, -Cl, -Br, -CN, hydroxy(C 1 -C 6 )alkyl, cyano(C 1 -C 6 )alkyl, (C 1 -C 3 alkoxy, halo(C 1 -C 3 )alkoxy ,(C 1 -C 6 )alkoxy(C 1 -C 3 )alkyl, phenyl and 5-6 membered heteroaryl.
• X is -O-, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.
• X is -S-, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.
• X is -SO-, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.
• X is -SO 2 -, and the values and specific values of the remainder of the variable are as described above in the 13 th specific embodiment.
• R 8 is independently (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 14 )cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, phenyl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 )cycloalkyl and (C 3 -C 7 )cycloheteroalkyl
• R 8 is hydroxy(C 1 -C 3 )alkyl and R 9 is -H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment.
• X is -O-. In another even more specific embodiment, X is -O-; and R 9 is -H, methyl or hydroxymethyl.
• R 8 is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl.
• substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 8 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 13 th specific embodiment. More particularly, X is -O-. Even more particularly, when R 9 is -H, R 8 is a (C 1 -C 3 )alkyl optionally substituted(C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is -O-.
• R 8 is a (C 2 -C 6 )alkenyl optionally substituted with1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.
• R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl.
• X is -O-. In another even more specific embodiment, X is -O-; and when R 9 is -H, R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl.
• R 9 is -H
• R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,
• X is -O-.
• X is -O-; and when R 9 is -H, R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cyclohetero
• X is -O-; when R 9 is -H, R 8 is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C
• R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.
• X is -O-. In another even more specific embodiment, X is -O-; and when R 9 is -H, R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 (C 1 -C 6 )alkyl.
• R 9 is -H
• R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl
• R 2 is aryl and the values and specific values of the remainder of the variable are as described in the 11 th specific embodiment. More specifically, R 2 is phenyl. In another more specfic embodiment, R 2 is indolinyl or benzoimidazole (connected through the benzene ring).
• X is -O-, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.
• X is -S-, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.
• X is -SO-, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.
• X is -SO 2 -, and the values and specific values of the remainder of the variable are as described above in the 14 th specific embodiment.
• R 8 is (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )cycloheteroalkyl, phenyl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl), hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy), halo(C 1 -C 3 )alkoxy, aryl, heteroaryl, (C 3 -C 8 )cycloalkyl and (C 3 -C 7 )cycloheteroalky
• R 8 is (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl and R 9 is -H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl.
• Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment.
• X is -O-.
• X is -O-; and R 8 and R 9 are -H, methyl or hydroxymethyl.
• R 8 is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -CI, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.
• substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 14 th specific embodiment. More particularly, X is -O-. Even more particularly, when R 9 is -H, R 8 is a (C 1 -C 3 )alkyl optionally substituted(C 3 -C 7 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran) and X is -0-.
• R 8 is a (C 2 -C 6 )alkenyl optionally substituted with1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.
• R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl.
• X is -O-. In another even more specific embodiment, X is -O-; and when R 9 is -H, R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl.
• R 9 is -H
• R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bridged (C 8 -C 13 )cycloheteroalkyl (such as 5,6,7,8-tetrahydroquinoline, 5,6,7,8-t
• X is -O-.
• X is -O-; and R 9 is -H and R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bicyclic fused or bicyclic bridged (C 8 -C 13 )cycloheteroal
• X is -O-
• R 9 is -H
• R8 is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6
• R 9 is -H and R 8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -CI, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy and halo(C 1 -C 3 )alkoxy.
• X is -O-. In another even more specific embodiment, X is -O-; and when R9 is -H, R8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 (C 1 -C 6 )alkyl.
• R9 is -H
• R8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran or and tetrahydropyran) or heteroaryl
• R 8 is (C 2 -C 6 )alkenyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 14 )cycloalkyl, (C 3 -C 13 )cycloheteroalkyl, phenyl or heteroaryl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl), hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy), halo(C
• R 8 and R 9 are both -H, (C 1 -C 3 )alkyl or hydroxy(C 1 -C 3 )alkyl. More specifically, R 8 and R 9 are -H, methyl or hydroxymethyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.
• R 8 is a (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 8 )cycloheteroalkyl.
• substituents are selected from the group consisting of (C 1 -C 6 )alkyl and (C 3 -C 7 )cycloheteroalkyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment. Even more particularly, R9 is -H and R8 is a (C 1 -C 3 )alkyl optionally substituted(C 3 -C 8 )cycloheteroalkyl (preferrably a tetrahydrofuran and tetrahydropyran).
• R 9 is -H and R 8 is a (C 2 -C 6 )alkenyl optionally substituted with1 to 3 substituents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 3 -C 8 ) cycloalkyl and (C 3 -C 7 )cycloheteroalkyl.
• R9 is -H and R8 is unsubstituted phenyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.
• R 9 is -H and R 8 is phenyl substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 3 )alkylcarbonyl and (C 1 -C 3 )alkoxycarbonyl.
• substituents are independently selected from -F, -Cl, -Br, -CN, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, acetyl, ethoxycarbonyl and hydroxymethyl. Values and specific values of the remainder of the variables are as described above in the 15 th specific embodiment.
• R 9 is -H and R 8 is monocylic (C 3 -C 8 )cyloalkyl (such as cyclopentyl and cyclohexyl), bicyclic fused (C 9 -C 14 )cycloalkyl (such as 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene), monocylic (C 3 -C 7 )cycloheteroalkyl (such as tetrahydrofuran, tetrahydropyran and piperidine), bi
• R9 is -H and R8 is tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-oxabicyclo[2.2.2]octane, each optionally substituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6
• R9 is -H and R8 is (C 3 -C 8 )cyloalkyl (preferrably cyclopentyl and cyclohexyl), (C 3 -C 7 )cycloheteroalkyl (preferrably tetrahydrofuran, or and tetrahydropyran) or heteroaryl (preferrably pyridinyl or thiophenyl), each optionally subsituted with 1 to 3 substitutents independently selected from the group consisting of -F, -Cl, -Br, -CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl
• R 10 is -CN, -F, -Cl, or -Br; and the remainder of the variables are as described above in the 16 th specific embodiment.
• R 8 and R 9 is -H, the other is phenyl, tetrahydrofuran, tetrahydropyran, cyclopentane, cyclohexane, cycloheptane, oxepane, 1,3-dioxane, piperidine, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, 5,6,7,8-tetrahydroquinoline, 5,6,7,8-tetrahydroisoquinoline, or 2-ox
• the compounds are listed in the following table: Compound No. STRUCTURE 1 2 2a 2b 3 4 5 6 7 8a 8b 9 10 11 12 13 14 15 16 17 18 19 19a 20 21 22 23 24 25a 25b 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 44a 44b 45 46 47 48 49 50 51a 51b 52 53 54 55a 55b 56 57 57a 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 72a 72b 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89a 89b 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113a 113b 114 115 116 117 118 119 120 121 122 123 124 125 126 127a 127b 128 129 130
• variable e.g., aryl, heterocyclyl, R 1 , R 2 , etc.
• Alkyl means a saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having the specified number of carbon atoms.
• (C 1 -C 6 )alkyl means a radical having from 1-6 carbon atoms in a linear or branched arrangement.
• “(C 1 -C 6 )alkyl” includes methyl, ethyl, propyl, butyl, pentyl, and hexyl. Also included within the definition of "alkyl” are those alkyl groups that are optionally substituted. Suitable subsitutions include, but are not limited to, -halogen, -OH, -CN, alkoxy, amino, cycloalkyl, aryl, heteroaryl, or aryloxy.
• Alkenyl means branched or straight-chain monovalent hydrocarbon radical containing at least one double bond and having specified number of carbon atoms. Alkenyl may be mono or polyunsaturated, and may exist in the E or Z onfiguration. Thus, "(C 2 -C 6 )alkenyl” means a radical having from 2-6 carbon atoms in a linear or branched arrangement.
• alkynyl means branched or straight-chain monovalent hydrocarbon radical containing at least one triple bond and having specified number of carbon atoms.
• (C 2 -C 6 )alkynyl means a radical having from 2-6 carbon atoms in a linear or branched arrangement.
• Cycloalkyl means a saturated aliphatic cyclic hydrocarbon radical having the specified number of carbon atoms. It can be monocyclic, bicyclic, polycyclic (e.g., tricyclic), fused, bridged, or spiro.
• monocyclic (C 3 -C 8 )cycloalkyl means a radical having from 3-8 carbon atoms arranged in a ring.
• Monocyclic (C 3 -C 8 )cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctane.
• Monocyclic ring systems have a single ring structure. They include saturated or unsaturated aliphatic cyclic hydrocarbon rings or aromatic hydrocarbon ring having the specified number of carbon atoms.
• the monocyclic ring system can optionally contain 1 to 3 heteroatoms in the ring structure and each heteroatom is independently selected from the group consisting O, N and S.
• heteroatom When the heteroatom is N, it can be subsituted with -H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc.
• the heteroatom When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e.
• monocyclic ring system examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctane, azetidine, pyrrolidine, piperidine, piperazine, hexahydropyrimidine, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, morpholine, thiomorpholine, thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-
• Bicyclic ring systems have two rings that have at least one ring atom in common.
• Bicyclic ring systems include fused, bridged and spiro ring systems.
• the two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof.
• the bicyclic ring sytems can optionally contain 1 to 3 heteroatoms in the ring structure and each heteroatom is independently selected from the group consisting O, N and S.
• heteroatom When the heteroatom is N, it can be subsituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc.
• the heteroatom When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. -S(O)- or -S(O) 2 -).
• a fused bicyclic ring system has two rings which have two adjacent ring atoms in common.
• the two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof.
• the first ring can be monocyclic cycloalkyl or moncyclic cycloheteroalkyl
• the second ring can a cycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or a monocyclic cycloheteroalkyl.
• the second ring can be a (C 3 -C 6 )cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• the second ring can be an aryl ring, e.g., phenyl.
• fused bicyclic ring systems include, but not limited to, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, 2,3-dihydro-1H-indene, octahydro-1H-indene, tetrahydronaphthalene, decahydronaphthalene, indoline, isoindoline, 2,3-dihydro-1H-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydrobenzo[d]thiazole, octahydrobenzo[d]oxazole, octahydro-1H-benzo[d]imidazole, octahydrobenzo[d]thiazole, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[3.1.0]hexane, 3-azabicyclo[3.2.0]heptane, 5,
• a spiro bicyclic ring system has two rings which have only one ring atom in common.
• the two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof.
• the first ring can be a monocyclic cycloalkyl or a monocyclic cycloheteroalkyl and the second ring can be a cycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or a monocyclic cycloheteroalkyl.
• sprial bicyclic ring system examples include, but are not limited to, spiro[2.2]pentane, spiro[2.3]hexane, spiro[3.3]heptane, spiro[2.4]heptane, spiro[3.4]octane, spiro[2.5]octane, azaspiro[4.4]nonane, 7-azaspiro[4.4]nonane, azasprio[4.5]decane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3-azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane.
• a bridged bicyclic ring system has two rings which have three or more adjacent ring atoms in common.
• the two rings can both be aliphatic (e.g., cycloalkyl or cycloheteroalkyl), both be aromatic (e.g., aryl or heteroaryl), or a combination thereof.
• the first ring can be a monocyclic cycloalkyl or a monocyclic cycloheteroalkyl and the other ring is a cycloalkyl, partially unsaturated carbocycle, aryl, heteroaryl or a monocyclic cycloheteroalkyl.
• bridged bicyclic ring system examples include, but are not limited to, bicyclo[1.1.0]butane, bicyclo[1.2.0]pentane, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptane, bicyclo[3.3.0]octane, bicyclo[4.2.0]octane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[3.3.2]decane bicyclo[3.3.3]undecane, azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane, azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.1]octane, 6-azabicyclo[3.2.1]octane and azabicyclo[
• Polycyclic ring systems have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common.
• Polycyclic ring systems include fused, bridged and spiro ring systems.
• a fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common.
• a spiro polycyclic ring system has at least two rings that have only one ring atom in common.
• a bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
• polycyclic ring system examples include, but not limited to, tricyclo[3.3.1.0 3,7 ]nonane (noradamantane) and tricyclo[3.3.1.1 3,7 ]decane (adamantane) and 2,3-dihydro-1H-phenalene.
• Cycloheteroalkyl means a saturated 4-12 membered ring containing 1 to 4 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one or more double bonds. It can be monocyclic, bicyclic, polycyclic (e.g. tricyclic), fused, bridged, or spiro.
• heteroatom When the heteroatom is N, it can be subsituted with H, alkyle, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc.
• the heteroatom When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. -S(O)- or -S(O) 2 -).
• Haloalkyl and halocycloalkyl include mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, and bromine.
• Heteroaryl means a monovalent heteroaromatic monocyclic or polycylic ring radical. Heteroaryl rings are 5- and 6-membered aromatic heterocyclic rings containing 1 to 4 heteroatoms independently selected from N, O, and S, and include, but are not limited to furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,2,5-thiadiazole, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole 1,1-dioxide, 1,3,4-thiadiazole, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyridazine, 1,2,4-triazine, 1,3,5-triazine, and tetrazole.
• Bicyclic heteroaryl rings are bicyclo[4.4.0] and bicyclo[4,3.0] fused ring systems containing 1 to 4 heteroatoms independently selected from N, O, and S, and include indolizine, indole, isoindole, benzo[b]furan, benzo[b]thiophene, indazole, benzimidazole, benzthiazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine.
• Alkoxy means an alkyl radical attached through an oxygen linking atom.
• (C 1 -C 4 )-alkoxy includes methoxy, ethoxy, propoxy, and butoxy.
• Aromatic means an unsaturated cycloalkyl ring system.
• Aryl means an aromatic monocyclic, or polycyclic carbocyclic ring system.
• Aryl systems include, but limited to, phenyl, naphthalenyl, fluorenyl, indenyl, azulenyl, and anthracenyl.
• Hetero refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O.
• a hetero ring may have 1, 2, 3, or 4 carbon atom members replaced by a heteroatom.
• Halogen used herein refers to fluorine, chlorine, bromine, or iodine.
• Carbocycle means 3-14 membered saturated or unsaturated aliphatic cyclic hydrocarbon ring.
• Cycloalkene a unsaturated and non-aromatic aliphatic cyclic hydrocarbon radical having the specified number of carbon atoms. It can be monocyclic, bicyclic, tricyclic, fused, bridged, or spiro.
• (C 3 -C 8 )cycloalkene means a radical having from 3-8 carbon atoms arranged in a ring.
• (C 3 -C 8 )cycloalkene includes cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
• Ring A is a 3-14 membered monocyclic ring system, 9-14 membered bicyclic ring system or 9-14 membered polycyclic ring system.
• the rings of the bicyclic and polycyclic ring systems can be fused, bridged or spiral.
• Ring A can be aromatic (e.g., aryl or heteroaryl) or aliphatic (saturated or unsaturated), provided that when Ring A is a monocyclic, ring, it can only be aliphatic.
• ring A can be a carbocycle such as a cycloalkene (e.g., cyclopentene, cyclohexene, cycloheptene or cyclooctene), a cycloalkane ring or a cycloheteroalkane ring as defined above.
• Ring A can optionally contain 1 to 3 heteroatoms each independently selected from O, S and N.
• heteroatom When the heteroatom is N, it can be subsituted with H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl (preferrably, -H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or (C 1 -C 3 )alkylcarbonyl), each of which can be optionally substituted with halogen, hydroxy, alkoxy, haloalkyl, alkyl, etc.
• the heteroatom When the heteroatom is S, it can be optionally mono- or di-oxygenated (i.e. - S(O)- or -S(O) 2 -).
• the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
• the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
• Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
• Pharmaceutically acceptable acidic/anionic salts include, the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,
• Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
• a suitable base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N.N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino
• the invention also includes various isomers and mixtures thereof.
• “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
• Stereoisomers are compounds which differ only in their spatial arrangement.
• the invention encompasses all such forms, including compounds in the form of essentially pure entiomers, racemic mixtures and tautomers, which includes forms not depicted structurally.
• a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, tautomers, geometric isomers or a combination thereof.
• Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
• "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable.
• Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms.
• the symbol “*” in a structural formula represents the presence of a chiral carbon center.
• R and “S”' represent the configuration of substituents around one or more chiral carbon atoms.
• R*" and “S*” denote the relative configurations of substituents around one or more chiral carbon atoms. When a chiral center is not defined as R or S, a mixture of both configurations is present.
• Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
• “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration.
• Atoms (other than H) attached to a carbocyclic ring may be in a cis or trans configuration.
• the substituents are on the same side in relationship to the plane of the ring; in the “trans” configuration, the substituents are on opposite sides in relationship to the plane of the ring.
• a mixture of "cis” and “trans” species is designated “cis/trans”.
• the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
• Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
• the stereochemistry of a disclosed compound is named or depicted by structure
• the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other stereoisomers.
• the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
• the compounds of the invention are BACE inhibitors for use in treating, preventing or ameliorating disorders or diseases characterized by elevated ⁇ -amyloid deposits or ⁇ -amyloid levels in a subject.
• diseases or disorders include, but not limited to, Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-typle (HCHWA-D), other neurodegenerative disorders and glaucoma.
• the present invention provides methods for modulating BACE and treating, preventing or ameliorating Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-typle (HCHWA-D) and other neurodegenerative disorders.
• Such methods comprises administering to a patient suffering from, suspected of suffering from or being susceptible to the disease or disorder an effective amount of the compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention also provides compounds for use in a method for the treatment of a disorder related to or associated with excessive BACE activity in a patient in need thereof which comprises administering to said patient an effective amount of the compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.
• Representative disorders include Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma. Certain of these diseases are characterized by production of ⁇ -amyloid deposits or neurofibrillary tangles.
• the present invention also provides compounds for use in methods for inhibiting the activity of BACE, comprising administering to a subject and/or contacting a receptor thereof with an effective amount of at least one compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention also provides compounds for use in methods of ameliorating ⁇ -amyloid deposits in a subject, comprising administering to said subject an effective amount of at least one compound of Structrual Formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention also provides compounds for use in methods of treating a disorder selected from the group consisting of Alzheimer's disease, cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, other neurodegenerative disorders, and glaucoma in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof.
• the disorder is Alzheimer's disease.
• the disorder is glaucoma.
• a pharmaceutical composition of the invention may, alternatively or in addition to a compound of Formula I or any formula of the invention described herein, comprise a pharmaceutically acceptable salt of a compound of Formula I or a prodrug or pharmaceutically active metabolite of such a compound or salt and one or more pharmaceutically acceptable carriers therefor.
• compositions of the invention are BACE inhibitors.
• Said compositions can contain compounds having a mean inhibition constant (IC 50 ) against BACE of between about 50 ⁇ M to about 0.01 nM; between about 10 ⁇ M to about 0.01 nM; between about 5 ⁇ M to about 0.01 nM; between about 1 ⁇ M to about 0.01 nM; between about 500 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; between about 50 nM to about 0.01 nM; or between about 5 nM to about 0.01 nM.
• IC 50 mean inhibition constant
• the invention includes compounds for use in a therapeutic method for treating or ameliorating an BACE mediated disorder in a subject in need thereof comprising administering to a subject in need thereof an effective amount of a compound of Formula I or any other formulas of the invention described herein, or the enantiomers, diastereomers, or salts thereof or composition thereof.
• Administration methods include administering an effective amount (i.e., an effective amount) of a compound or composition of the invention at different times during the course of therapy or concurrently in a combination form.
• the methods of the invention include all known therapeutic treatment regimens.
• the term "subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
• the subject is a human in need of treatment.
• the term “treating” or “treatment” refers to obtaining desired pharmacological and/or physiological effect.
• the effect can be prophylactic or therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder; delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome; or partially or totally delaying, inhibiting or reducing the likelihood of the onset or development of disease, disorder or syndrome.
• Effective amount means that amount of active compound agent that elicits the desired biological response in a subject. Such response includes alleviation of the symptoms of the disease or disorder being treated.
• the effective amount of a compound of the invention in such a therapeutic method is from about 0.01 mg/kg/day to about 1000 mg/kg/day, from about 0.1 mg/kg/day to about 100 mg/kg/day, from about 0.5 mg/kg/day to about 50 mg/kg/day, or from about 1 mg/kg/day to 10 mg/kg/day.
• “Pharmaceutically acceptable carrier” means compounds and compositions that are of sufficient purity and quality for use in the formulation of a composition of the invention and that, when appropriately administered to an animal or human, do not produce an adverse reaction.
• BACE mediated disorder or disease includes disorders or diseases associated with the elevated expression or overexpression of BACE and conditions that accompany such diseases.
• An embodiment of the invention includes administering ⁇ -secretase inhibiting compound of Formula I or any formula of the invention described herein or a composition thereof in a combination therapy with one or more additional agents for the treatment of Alzheimer's disease.
• Additional agents include, but are not limited to: cholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine; memantine; tacrine; antidepressants, such as citalopram, fluoxetine, paroxetine, sertraline and trazodone; anxiolytics, such as lorazepam and oxazepam; antiphychotics, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone.
• Combination therapy includes co-administration of the compound of the invention and said other agent, sequential administration of the compound and the other agent, administration of a composition containing the compound and the other agent, or simultaneous administration of separate compositions containing of the compound and the other agent.
• the invention further includes the process for making the composition comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques.
• compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), and injection (intraperitoneally, subcutaneously, intramuscularly, intratumorally, or parenterally).
• the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.
• a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration
• compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.
• forms useful for ocular administration include sterile solutions or ocular delivery devices.
• forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
• compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration.
• an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic administration.
• the dosage form containing the composition of the invention contains an effective amount of the active ingredient necessary to provide a therapeutic effect.
• the composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration.
• the composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed.
• the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation.
• the oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention.
• the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).
• pharmaceutical carriers such as a
• Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta-lactose), corn sweeteners and natural and synthetic gums (e.g., acacia and tragacanth).
• Disintegrating agents include starch, methyl cellulose, agar, and bentonite.
• Tablets and capsules represent an advantageous oral dosage unit form. Tablets may be sugarcoated or filmcoated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect.
• the dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component.
• the two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release.
• a layer which resists disintegration in the stomach such as an enteric layer
• enteric and non-enteric layer or coating materials such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof may be used.
• Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).
• a biodegradable slow release carrier e.g., a polymeric carrier
• a pharmaceutically acceptable non-biodegradable slow release carrier e.g., an ion exchange carrier
• Biodegradable and non-biodegradable slow release carriers are well known in the art.
• Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent.
• a suitable environment e.g., aqueous, acidic, basic and the like
• Such particles degrade/dissolve in body fluids to release the active compound(s) therein.
• the particles are preferably nanoparticles (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter).
• a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent.
• the resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion.
• the organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.
• the compound of Formula I may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin.
• the liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums.
• sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.
• a parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier.
• Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation.
• aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution.
• Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl).
• a sterile, non-volatile oil may be employed as a solvent or suspending agent.
• the parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient.
• Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents.
• injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
• Compounds of the invention may be administered intranasally using a suitable intranasal vehicle.
• Compounds of the invention may also be administered topically using a suitable topical transdermal vehicle or a transdermal patch.
• the composition is preferably in the form of an ophthalmic composition.
• the ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
• the compositions are sterile and aqueous based, using purified water.
• an ophthalmic composition may contain one or more of: a) a surfactant such as a polyoxyethylene fatty acid ester; b) a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the composition in a container containing nitrogen and optionally including a free oxygen absorber such as Fe), an anti-oxidant such as butylated hydroxyanisol, ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at a concentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at a concentration of about 0.01 to 0.5% (wt/vol); and e) other excipients such as an isotonic agent, buffer, preservitol, typically at a
• a glass pressure tube was charged with a mixture 6-bromo-2-(tetrahydro-2 H- pyran-3- yl)chroman-4-one (4 g, 13.03 mmol), KCN (1.7 g, 26.06 mmol), and (NH 4 ) 2 CO 3 (9.4 g, 97.7 mmol).
• Formamide (30 mL) was added to fill the tube nearly completely. The mixture was heated at 80 °C for 2 days. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then redissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Step 7 2'-amino-6-bromo-1'-methyl-2-(tetrahydro-2 H -pyran-3-yl)spiro[chroman-4,4'-imidazol]-5'(1' H )-one
• Step 8 3-(2'-amino-1'-methyl-5'-oxo-2-(tetrahydro-2 H -pyran-3-yl)-1',5'-dihydrospiro[chro man-4,4'-imidazole]-6-yl)benzonitrile ( compound 1 )
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-(tetrahydro-2 H -pyran-3-yl)spiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120 °C for 30 minutes.
• Pd(PPh 3 ) 4 (60 mg, 0.052 mmol) in a 100 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1'H)-one (100 mg, 0.26 mmol) in toluene (15.6 mL), Na 2 CO 3 (2 N, 7.8 mL), and 4-cyanophenylboronic acid (76.5 mg, 0.52 mmol). The mixture was refluxed under Ar for 3 ⁇ 5 h.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyano-4-fluorophenylboronic acid (17 mg, 0.104 mmol). The mixture was heated under Ar at 120 °C under microwave for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (24 mg, 0.104 mmol). The mixture was heated at 120 °C in a microwave reactor for 0.5 h.
• a glass pressure tube was charged with a mixture of 6-bromo-2-thiophen- 2-ylchroman-4-one (1.5 g, 48.7 mmol), KCN (0.63 g, 97.4 mmol), and (NH 4 ) 2 CO 3 (3.27 g, 34.1 mmol).
• Formamide (30 mL) and DMF (10 mL) were added to fill the tube nearly completely.
• the mixture was heated at 70 °C for 2 h with microwave.
• the reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Step 6 3-((2 S ,4 S )-2'-amino-1'-methyl-5'-oxo-2-(thiophen-2-yl)-1',5'-dihydrospiro[chroman-4,4'-imidazole]-6-yl)benzonitrile
• a steel bomb was charged with a mixture of 6-bromo-2-(2-fluorophenyl)chroman-4-one (2 g, 6.25 mmol), KCN (0.82 g, 12.5 mmol), and (NH 4 ) 2 CO 3 (4.5 g, 46.87 mmol).
• Formamide 25 mL is added to fill the steel bomb nearly completely.
• the mixture was heated at 70°C for 48 h then at 110°C for another 8 h.
• the reaction mixture was then cooled and poured over ice. Acidification with concentrated HCI yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Pd(PPh 3 ) 4 (3.84 mg, 0.1 mmol) was added to the solution of 2'-amino-6-bromo-2-(2-fluorophenyl)-1'-methylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (42 mg, 0.1 mmol) and 3-cyanophenylboronic acid (18.3 mg, 0.12 mmol) in dimethy-benzene (6.6 mL) and an aqueous solution of Na 2 CO 3 (2 M, 0.23 mL). The mixture was heated at 90°C in an oil bath overnight.
• Pd(PPh 3 ) 4 (40 mg, 0.10 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-ethyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (42 mg, 0.10 mmol) in toluene (5 mL), Na 2 CO 3 (2 N, 2 mL), and 4-cyanophenylboronic acid (31 mg, 0.21 mmol). The mixture refluxed under Ar overnight.
• Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2- phenylspiro[chroman-4,4'- imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-methoxyphenylboronic acid (16 mg, 0.104 mmol). The mixture was heated under 120 °C under Ar using microwave for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and pyridin-3-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated under microwave at 120 °C for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-amino-5-cyanophenylboronic acid hydrochloride (21 mg, 0.104 mmol). The mixture was heated at 120 °C under microwave reactor for 0.5 h.
• Step 1 6-bromo-1'-(cyclohexylmethyl)-2'-(cyclohexylmethylthio)-2-phenylspirochroman-4,4'-imidazol]-5'(1' H )-one
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-brom0-1'-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (30 mg, 0.064 mmol) in 1,4-dioxane (1.5 mL), Cs 2 CO 3 (2 N, 0.5 mL) and 3-cyanophenylboronic acid (19 mg, 0.128 mmol). The mixture was heated at 120 °C under microwave reactor for 0.5 h.
• a glass pressure tube was charged with a mixture of 6-bromo-2-(4-fluoro-phenyl)-chroman-4-one (1.5 g, 4.7 mmol), KCN (0.6 g, 9.4 mmol), and (NH 4 ) 2 CO 3 (3.16 g, 32.9 mmol).
• Formamide 40 mL was added to fill the tube nearly completely.
• the mixture was heated at 70 °C for 2 h with microwave.
• the reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then redissolved in ethyl acetate, dried over Na 2 SO 4 and filtered.
• Step 6 3-((2 S ,4 S )-2'-amino-2-(4-fluorophenyl)-1'-methyl-5'-oxo-1',5'-dihydrospiro [chroman-4,4'-imidazole]-6-yl)benzonitrile(6 mg, 10%) and 3-(2'-amino-2-(4-fluorophenyl)- 1'-methyl-5'-oxo-1',5'-dihydrospiro[chrom- an-4,4'-imidazole]-6-yl)benzonitrile ( 19 ).
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL of tube under Ar 2 was treated sequentially with 2'-amino-6- bromo-2-(4-fluorophenyl)-1'-methylspiro[chroman-4,4'-imidazol]-5'(1'H)-one (40 mg, 0.099 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-cyanophenylboronic acid (29 mg, 0.197 mmol). The mixture was heated under microwave at 120 °C for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 2-chloro-5-cyanophenylboronic acid (18.9 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar under microwave for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (15 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (50 mg, 0.13 mmol) in 1,4-dioxane (2 mL), Cs 2 CO 3 (2 N, 0.6 mL) and 3-vinylphenylboronic acid (29 mg, 0.19 mmol). The mixture was heated at 120 °C under microwave reactor for 0.5 h.
• a steel bomb was charged with a mixture of 6-bromo-2-(3-methoxyphenyl) chroman-4-one (3.3 g, 9.94 mmol), KCN (1.29 g, 20 mmol), and (NH 4 ) 2 CO 3 (7.15 g, 75 mmol).
• Formamide 25 mL was added to fill the steel bomb nearly completely. The mixture was heated at 70 °C for 48 h then at 110 °C for another 4 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl gave a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-fluoro-3-(trifluoromethoxy) phenylboronic acid (20 mg, 0.106 mmol). The mixture was heated at 120 °C under microwave reactor for 0.5 h.
• Pd(PPh 3 ) 2 Cl 2 (5 mg, 0.007mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(hydroxymethyl)phenylboronic acid (17 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in a microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and phenylboronic acid (16 mg, 0.1 mmol). The mixture was heated under microwave at 120 °C for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(methylsulfonyl)phenylboronic acid (20.8 mg, 0.104 mmol). The mixture was heated at120 °C under Ar in a microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.014 mmol) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(cyanomethyl)phenylboronic acid (16.7 mg, 0.104 mmol). The mixture was heated at 120 °C in a microwave reactor for 0.5 h.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(trifluoromethyl) phenylboronic acid (19.7 mg, 0.1 mmol). The mixture was heated under microwave at 120 °C for 30 minutes.
• a steel pressure tube was charged with a mixture of 6-bromo-2-methyl-2-phenyl-chroman- 4-one (6.2 g, 19.6 mmol), KCN (2.55 g, 39.2 mmol), and (NH 4 ) 2 CO 3 (14.1 g, 147 mmol).
• Formamide 70 mL was added to fill the pressure tube nearly completely.
• the mixture was heated at 70 °C for 48 h then at 110 °C for another 24 h.
• the reaction mixture was then cooled and poured over ice. After acidification with concentrated HCl, the mixture was extracted with ethyl acetate (150 mL*3). The combined organic layers were dried over Na 2 SO 4 and filtered.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(hydroxymethyl)phenylboronic acid (15 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 2-cyanophenylboronic acid (15.3 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in a microwave reactor for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(2-methoxyethylcarbamoyl)phenylboronic acid (23.2 mg, 0.104 mmol). The mixture was heated at120 °C under Ar in a microwave reactor for 30 min.
• a steel bomb was charged with a mixture of 6-bromo-2-(3-flurophenyl)chroman-4-one (3.2 g, 0.01 mol), potassuim cyanide (1.95 g, 0.03 mmol), and (NH 4 ) 2 CO 3 (7.2 g, 0.075 mmol).
• Formamide (20mL) was added to fill the steel bomb nearly completely.
• the mixture was heated at 70 °C for 48 h then at 110 °C for another 8 h.
• the reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl was performed to give a precipitate which is filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(dimethylcarbamoyl) phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in a microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-fluoro-3-(2-hydroxyethylcarbamoyl)phenylboronic acid (23 mg, 0.106 mmol). The mixture was heated at 120 °C in a microwave reactor for 0.5 h.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-acetamidophenylboronic acid (17.9 mg, 0.1 mmol). The mixture was heated at 120 °C in a microwave reactor for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(acetamidomethyl)phenylboronic acid (19.3 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 minutes.
• Anhydrous aluminum chloride (84 g, 0.486 mol) was suspended in methylene chloride (1200 mL), and then acetyl chloride (49.2 g, 0.629 mol) was added while stirring and cooling on ice. The mixture was stirred for 20 minutes while cooling on ice and 4-bromophenol (98 g, 0.57 mol) was added. The reaction mixture was stirred at room temperature for 1 h, and then ice water was added and extraction was performed with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate.
• a glass pressure tube was charged with a mixture of 6-bromo-2-phenyl-chroman-4-one (7.6 g, 25 mmol), KCN (3.25 g, 50 mmol), and (NH 4 ) 2 CO 3 (18 g, 187.5 mmol).
• Formamide 80 mL was added to fill the pressure tube nearly completely. The mixture was heated at 70°C for 24 h then at 110°C for another 48 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• a glass pressure tube was charged with a mixture of 6-bromo-2-phenyl-chroman-4-one (15.1 g, 50 mmol), KCN (6.5 g, 100 mmol), and (NH 4 ) 2 CO 3 (36 g, 375 mmol).
• Formamide 80 mL was added to fill the pressure tube nearly completely.
• the mixture was heated at 70 °C for 24 h then at 110 °C for another 48 h.
• the reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3 -( N , N- dimethylsulfamoyl)phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120 °C in a microwave reactor for 0.5 h.
• a steel bomb was charged with a mixture of 6-bromo-2-(3-methoxyphenyl)chroman-4-one (2 g, 6 mmol), KCN (770 mg, 12 mmol), and (NH 4 ) 2 CO 3 (4 g, 42 mmol).
• Formamide (20 mL) was added to fill the pressure tube nearly completely. The mixture was heated at 70 °C for 72 h then at 110 °C for another 5 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1'H)-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(2-cyanoethyl-carbamoyl)phenylboronic acid (22 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 mins.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-( N- methylsulfamoyl) phenylboronic acid (23 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(methylsulfonyl)phenylboronic acid (20.8 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(methylcarbamoyl)phenylboronic acid (18.6 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )- one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(methylsulfonamido) phenylboronic acid (22 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in a microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(methoxymethyl)phenylboronic acid (16.6 mg, 0.1 mmol). The mixture was heated at 120 °C in a microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.05 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(butylcarbamoyl)phenylboronic acid (23 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 mins.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(trifluoromethyl)phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in a microwave reactor for 30 minutes.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and pyridin-4-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120 °C for 30 min.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2'- amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1'H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(isobutylcarbamoyl)- phenyl- boronic acid (23 mg, 0.1 mmol). The mixture was heated at 120 °C in a microwave reactor for 30 mins.
• Pd(PPh 3 ) 2 Cl 2 (10 mg) in a 10 mL of tube under Ar 2 was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 3-(pyrrolidine-1-carbonyl)phenylboronic acid (10 mg, 0.045 mmol). The mixture was heated at 120 °C in a microwave reactor for 0.5 h.
• Pd(PPh 3 ) 2 Cl 2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2'-amino-6-bromo-1'-methyl-2-phenylspiro[chroman-4,4'-imidazol]-5'(1' H )-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs 2 CO 3 (2 N, 0.3 mL) and 4-(methylsulfonamidomethyl) phenylboronic acid (24 mg, 0.104 mmol). The mixture was heated at 120 °C under Ar in a microwave reactor for 30 minutes.
• a steel bomb was charged with a mixture of 6-bromo-2-(2-fluorophenyl)chroman-4-one (2 g, 6.25 mmol), KCN (0.82 g, 12.5 mmol), and (NH 4 ) 2 CO 3 (4.5 g, 46.87 mmol).
• Formamide 25 mL was added to fill the steel bomb nearly completely. The mixture was heated at 70 °C for 48 h then at 110°C for another 12 h. The reaction mixture was then cooled and poured over ice. Acidification with concentrated HCl yielded a precipitate which was filtered, washed twice with water, and then dissolved in ethyl acetate, dried over Na 2 SO 4 , and filtered.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Animal Behavior & Ethology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Ophthalmology & Optometry (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=41651370

Family Applications (1)

Country Status (6)

Cited By (1)

Families Citing this family (50)

Family Cites Families (35)

• 2009
  • 2009-08-14 US US13/059,879 patent/US8450308B2/en active Active
  • 2009-08-14 WO PCT/US2009/004686 patent/WO2010021680A2/en active Application Filing
  • 2009-08-14 EP EP09789150.1A patent/EP2324032B1/en not_active Not-in-force
  • 2009-08-17 TW TW098127567A patent/TW201020256A/zh unknown
  • 2009-08-19 UY UY0001032062A patent/UY32062A/es not_active Application Discontinuation
  • 2009-08-19 AR ARP090103187A patent/AR073046A1/es unknown
• 2013
  • 2013-04-22 US US13/867,590 patent/US8921359B2/en active Active

Also Published As

Similar Documents

Legal Events